Project Summary/Abstract Binge eating disorder (BED), a formal DSM-5 diagnosis, is a prevalent, refractory, and serious health problem experienced by men and women and with heightened psychiatric and medical comorbidity. Although BED is associated strongly with obesity, BED is distributed across weight categories. Nearly all treatment trials for BED have required the presence of co-morbid obesity despite epidemiological estimates that 58% of those with BED are not obese. Current pharmacological treatment options are limited and the sole FDA-approved medication for BED has a ?Limitation of Use? for weight loss and treating obesity. Ideally, an optimal pharmacological approach for BED would reduce binge eating in those with and without obesity, and have the added benefit of reducing weight in those with co-morbid obesity. The combined use of naltrexone HCI and bupropion HCI (NB) was developed to target alterations in the hypothalamic melanocortin system and the brain reward system, with the two compounds hypothesized to work synergistically to reduce food intake. Although NB targets systems highly relevant for those with BED, its efficacy for reducing binge eating is unknown. Our pilot data shows that NB reduces rates of binge eating behavior as well as reduces weight in those with co-morbid BED+obesity. The primary aim is to conduct a double-blind, placebo-controlled parallel group RCT to evaluate the efficacy of NB versus placebo to reduce binge eating in patients with BED, stratified by obesity status (n=50 per cell, n=200 total) for a 12-week treatment period and a 12-month follow-up period. The second primary aim evaluates mechanisms underlying the effect of NB on binge eating. An established human laboratory paradigm will be used to assess eating behaviors including the ability to resist eating preferred high-caloric food and subsequent over-eating. Potential mechanisms involved in both homeostatic and hedonic aspects of eating will be examined. We hypothesize that potential medication-related changes in eating behavior, eating peptides and food craving assessed in the laboratory will mediate clinical outcomes during the 12-week RCT (i.e., rates of binge eating). The third, and exploratory aim, assesses eating and drinking behavior, food craving, and mood `in the field' during the first 6 weeks of NB treatment in a subset of participants (n=60) with the use of an innovative biosensor system. We will examine whether medication-related changes in naturalistic eating behavior relate to clinical outcomes (i.e., rates of binge eating). This innovative interdisciplinary study will: (1) Provide the first test of the therapeutic potential and related mechanisms of NB for BED in patients with obesity and without obesity. (2) Identify correlates and potential mechanisms underlying the effect of NB on binge eating. Evaluating outcomes with innovative human laboratory and with novel field assessments using wearable biosensors will optimize internal and external validity and provide the most comprehensive multi-modal assessment of any treatment study for BED to date.